Targeting DEPTOR in multiple myeloma

多发性骨髓瘤中的 DEPTOR 靶向治疗

基本信息

批准号：
8442174
负责人：
ALAN K LICHTENSTEIN
金额：
$ 13.38万
依托单位：
BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8442174
关键词：
1-Phosphatidylinositol 3-Kinase Address Apoptosis Autophagocytosis Binding Binding Proteins Biological Assay Cancer Patient Cell Cycle Cell Cycle Progression Cell Cycle Proteins Cell Line Cell Survival Cells Chemicals Clinical Trials Complex Data Depressed mood Disease Feedback Genetic Translation Goals Growth Growth Factor Hybrids In Vitro Inhibition of Apoptosis Laboratories Malignant - descriptor Malignant Neoplasms Marrow Molecular Multiple Myeloma Multiprotein Complexes New Agents Nutrient PI3K/AKT PTEN gene Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Plasma Cells Play Process Proteins Proto-Oncogene Proteins c-akt Reading Repression Robotics Role Screening procedure Signal Transduction Specimen Stress Testing Translations Tumor Subtype Tumor Suppressor Proteins Xenograft Model Yeasts high throughput screening human FRAP1 protein improved in vitro Assay in vivo inhibitor/antagonist knock-down mTOR Inhibitor novel prevent public health relevance research clinical testing resistance mechanism screening therapeutic target tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The proposal addresses the potential of targeting the binding of DEPTOR to mTOR in TORC complexes in multiple myeloma cells. The preliminary results support the hypothesis that compounds can be identified in a yeast-hybrid high throughput screen that inhibit this binding. Once inhibited, we anticipate a subsequent dampening of the PI3-kinase/AKT pathway and induction of myeloma cell apoptosis. DEPTOR function is critical for survival of a subset of multiple myeloma clones consisting of approximately 30% of patients. This specific subset of patients can be identified by readily available clinical testing on their marrow malignant plasma cells. Thus, we part from the premise that identified compounds that inhibit DEPTOR-mTOR binding could be developed for effective targeted therapy for these patients. To further address DEPTOR as a therapeutic target, we will test the screening positive 'hits' for molecular effects in myeloma cells as well as anti-myeloma efficacy in vitro and in vivo in xenograft models.

描述（由申请人提供）：该提案提出了在多发性骨髓瘤细胞的 TORC 复合物中靶向 DEPTOR 与 mTOR 结合的潜力。初步结果支持这样的假设：可以在酵母杂交高通量筛选中鉴定出抑制这种结合的化合物。一旦受到抑制，我们预计随后会抑制 PI3 激酶/AKT 通路并诱导骨髓瘤细胞凋亡。 DEPTOR 功能对于由大约 30% 的患者组成的多发性骨髓瘤克隆子集的生存至关重要。这种特定的患者亚群可以通过对其骨髓恶性浆细胞进行现成的临床测试来识别。因此，我们的前提是可以开发出抑制 DEPTOR-mTOR 结合的化合物来对这些患者进行有效的靶向治疗。为了进一步将 DEPTOR 作为治疗靶点，我们将在异种移植模型中测试筛选阳性“命中”的骨髓瘤细胞中的分子效应以及体外和体内的抗骨髓瘤功效。